White fine crystalline powder, easily soluble in water and ethanol.
pharmachologic effect

Antiepileptic agent, has a central muscle relaxant and sedative effect. The mechanism of action is associated with an increase in the content of GABA in the central nervous system (due to inhibition of GABA transferase, as well as a decrease in GABA reuptake in the brain), resulting in a decrease in excitability and convulsive readiness of the motor areas of the brain. According to another hypothesis, it acts on the sites of postsynaptic receptors, imitating or enhancing the inhibitory effect of GABA. A possible direct effect on membrane activity is associated with changes in K+ conductivity. Improves the mental state and mood of patients, has antiarrhythmic activity.
Pharmacokinetics

Absorption - high, food slightly reduces the rate of absorption; bioavailability - 100%. TCmax capsules and syrup - 1-4 hours, tablets - 3-4 hours, controlled release tablets - 2-8 hours, with intravenous administration - by the end of 1 hour of infusion. Css is achieved on 2-4 days of admission (depending on the intervals between doses). Therapeutic plasma concentrations range from 50-150 mg/l. Pharmacological and therapeutic effects when using controlled release forms are not always dependent on plasma concentration. The volume of distribution is 0.2 l / kg. Communication with plasma proteins - 90-95% (at plasma concentrations up to 50 mg / l), at a concentration of 50-100 mg / l it decreases to 80-85%; with uremia, hypoproteinemia and cirrhosis of the liver, plasma protein binding is also reduced.

Penetrates through the placental barrier and BBB; excreted in breast milk (concentration in breast milk is 1-10% concentration in maternal plasma). The content in the CSF correlates with the size of the non-protein-bound fraction. Metabolized by glucuronidation and oxidation in the liver, T1 / 2 - 8-22 hours.

Valproic acid (1-3%) and its metabolites (in the form of conjugates, oxidation products, including ketometabolites) are excreted by the kidneys; small amounts are excreted in faeces and exhaled air.

When combined with other medicinal drugs, T1 / 2 can be 6-8 hours due to the induction of metabolic enzymes, in patients with impaired liver function, elderly patients and children under 18 months, it can be much longer.

The prolonged form is characterized by the absence of latent absorption time, slow absorption, lower (by 25%), but relatively more stable plasma concentration between 4 and 14 hours.
Indications for use

Epilepsy of various origins.

Epileptic seizures (including generalized and partial seizures, as well as against the background of organic brain diseases).

Changes in character and behavior (due to epilepsy).

Febrile convulsions (in children), children's tic.

Manic-depressive psychosis with a bipolar course, not amenable to treatment with Li + drugs or other drugs.

Specific syndromes (West, Lennox-Gastaut).
Contraindications

Hypersensitivity, liver failure, acute and chronic hepatitis, pancreatic dysfunction, porphyria, hemorrhagic diathesis, severe thrombocytopenia, lactation.
Carefully

Inhibition of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia), organic diseases of the brain, diseases of the liver and pancreas in history; hypoproteinemia, mental retardation in children, congenital fermentopathy, renal failure, pregnancy, childhood up to 3 years.
Dosing regimen

Inside, during meals or immediately after meals, without chewing, drinking a small amount of water, 2-3 times a day. The syrup can be mixed with any liquid or added to a small amount of food.

The initial dose for monotherapy for adults and children weighing more than 25 kg is 5-15 mg / kg / day, then this dose is gradually increased by 5-10 mg / kg / week. Maximum dose- 30 mg / kg / day (may be increased if it is possible to control plasma concentration up to 60 mg / kg / day).

In combination therapy in adults - 10-30 mg / kg / day, followed by an increase in dose by 5-10 mg / kg / week.

For children weighing less than 25 kg, the average daily dose with monotherapy - 15-45 mg / kg, maximum - 50 mg / kg. Depending on age: newborns - 30 mg / kg, from 3 to 10 years - 30-40 mg / kg / day, up to 1 year - in 2 doses, in older ones - in 3 doses. In combination therapy - 30-100 mg / kg / day.

Children weighing less than 20 kg should not use controlled release tablets.

In / in the jet, 400-800 mg or in / in the drip, at the rate of 25 mg / kg for 24, 36, 48 hours. When deciding to switch to / in the introduction after oral administration, the first administration is carried out at a dose of 0.5-1 mg / kg / h 4-6 hours after the last oral administration.
Side effect

From the side of the central nervous system: tremor; rarely - changes in behavior, mood or mental state (depression, fatigue, hallucinations, aggressiveness, hyperactivity, psychosis, unusual agitation, restlessness or irritability), ataxia, dizziness, drowsiness, headache, encephalopathy, dysarthria, enuresis, stupor, impaired consciousness, coma.

From the senses: diplopia, nystagmus, flickering "flies" before the eyes.

From the side digestive system: nausea, vomiting, gastralgia, decreased appetite or increased appetite, diarrhea, hepatitis; rarely - constipation, pancreatitis, up to severe lesions with a fatal outcome (in the first 6 months of treatment, more often for 2-12 weeks).

On the part of the hematopoietic organs and the hemostasis system: inhibition of bone marrow hematopoiesis (anemia, leukopenia); thrombocytopenia, a decrease in the content of fibrinogen and platelet aggregation, leading to the development of hypocoagulation (accompanied by prolongation of bleeding time, petechial hemorrhages, bruising, hematomas, bleeding, etc.).

From the side of metabolism: decrease or increase in body weight.

allergic reactions: skin rash, urticaria, angioedema, photosensitivity, malignant exudative erythema (Stevens-Johnson syndrome).

Laboratory indicators: hypercreatininemia, hyperammonemia, hyperglycinemia, hyperbilirubinemia, a slight increase in the activity of "liver" transaminases, LDH (dose-dependent).

From the side endocrine system: dysmenorrhea, secondary amenorrhea, increased mammary glands, galactorrhea.

Others: peripheral edema, alopecia.
Overdose

Symptoms: nausea, vomiting, dizziness, diarrhea, impaired respiratory function, muscle hypotension, hyporeflexia, miosis, coma.

Treatment: gastric lavage (no later than 10-12 hours), activated charcoal, forced diuresis, maintenance of vital functions, hemodialysis.
Interaction

Valproic acid enhances the effects, incl. side effects, other antiepileptic drugs (phenytoin, lamotrigine), antidepressants, antipsychotic drugs (neuroleptics), anxiolytics, barbiturates, MAO inhibitors, thymoleptics, ethanol. The addition of valproic acid to clonazepam in isolated cases can lead to an increase in the severity of the absence status.

With the simultaneous use of valproic acid with barbiturates or primidone, an increase in the concentration of the latter in plasma is noted.

Increases T1 / 2 of lamotrigine (suppresses liver enzymes, causes a slowdown in the metabolism of lamotrigine, as a result of which T1 / 2 is extended to 70 hours in adults and up to 45-55 hours in children).

Reduces the clearance of zidovudine by 38%, while its T1 / 2 does not change.

Tricyclic antidepressants, MAO inhibitors, antipsychotic drugs (neuroleptics), etc. Drugs that lower the seizure threshold reduce the effectiveness of valproic acid.

When combined with salicylates, there is an increase in the effects of valproic acid (displacement from the connection with plasma proteins), enhances the effect of antiplatelet agents (ASA) and indirect anticoagulants.

When combined with phenobarbital, phenytoin, carbamazepine, mefloquine, the content of valproic acid in the blood serum decreases (metabolism acceleration).

Felbamate increases the concentration of valproic acid in plasma by 35-50% (dose adjustment is required).

With the simultaneous use of valproic acid with ethanol and other drugs that depress the central nervous system (tricyclic antidepressants, MAO inhibitors and antipsychotic drugs), it is possible to increase the depression of the central nervous system.

Ethanol and other hepatotoxic drugs increase the likelihood of liver damage.

Valproic acid does not cause the induction of microsomal liver enzymes and does not reduce the effectiveness of oral contraceptives.

Myelotoxic drugs - increased risk of inhibition of bone marrow hematopoiesis.
special instructions

During treatment, it is advisable to monitor the activity of "liver" transaminases, bilirubin concentrations, peripheral blood patterns, blood platelets, the state of the blood coagulation system, amylase activity (every 3 months, especially when combined with other antiepileptic drugs).

For patients receiving other antiepileptic drugs, the transition to valproic acid should be carried out gradually, reaching a clinically effective dose after 2 weeks, after which it is possible to gradually cancel other antiepileptic drugs. In patients who have not received treatment with other antiepileptic drugs, a clinically effective dose should be reached after 1 week.

Development risk side effects from the side of the liver is increased during combined anticonvulsant therapy, as well as in children.

Drinks containing ethanol are not allowed.

Before surgery is necessary general analysis blood (including platelet count), determination of bleeding time, coagulogram parameters.

If symptoms of an "acute" abdomen occur during treatment, it is recommended to determine the activity of amylase in the blood before the start of surgery to exclude acute pancreatitis.

During treatment, one should take into account the possible distortion of the results of urine tests in diabetes mellitus (due to an increase in the content of ketone bodies), indicators of thyroid function.

With the development of any acute serious side effects, it is necessary to immediately discuss with the doctor the advisability of continuing or stopping treatment.

To reduce the risk of developing dyspeptic disorders, it is possible to take antispasmodics and enveloping drugs.

Abrupt discontinuation of valproic acid may lead to an increase in epileptic seizures.

During the period of treatment, care must be taken when driving and engaging in other potentially dangerous species activities that require increased concentration of attention and speed of psychomotor reactions.

Valproic acid

prolonged-release film-coated tablets

antiepileptic agent.

Antiepileptic drug, has a central muscle relaxant and sedative effect. Shows antiepileptic activity in various types epilepsy.
The main mechanism of action seems to be associated with the effect of valproic acid on the GABAergic system: the drug increases the content of GABA in the central nervous system (CNS) and activates GABAergic transmission.
Therapeutic efficacy begins with a minimum concentration of 40-50 mg/l and can reach 100 mg/l. At a concentration of more than 200 mg / l, a dose reduction is necessary.
Pharmacokinetics
The bioavailability of the drug is about 100%. Distributed mainly into the blood and extracellular fluid. Valproic acid penetrates into the cerebrospinal fluid and through the blood-brain barrier.
The half-life is 15-17 hours. Therapeutic efficacy is manifested at plasma concentrations of 40 to 100 mg / l. At levels above 200 mg / l, a dose reduction is necessary. Equilibrium plasma concentration is reached after 3-4 days of administration.
Communication with plasma proteins - 90-95% (at plasma concentrations up to 50 mg / l), at a concentration of 50-100 mg / l it decreases to 80-85%; with uremia, hypoproteinemia and cirrhosis of the liver, plasma protein binding is also reduced. It is excreted mainly in the urine as a glucuronide and by beta-oxidation in a conjugated form.
Valproic acid is not an inducer of enzymes of the cytochrome P450 metabolic system. Unlike most other antiepileptic drugs, it does not affect the degree of both its own biotransformation and the biotransformation of other substances, such as estrogens, progestogens and vitamin K antagonists.
The prolonged form is characterized by no absorption delay time, prolonged absorption, identical bioavailability, lower (by 25%), but relatively more stable plasma concentration between 4 and 14 hours after administration, a more linear correlation between dose and plasma concentration of the drug.

In adults, as monotherapy or in combination with other antiepileptic drugs:
- treatment of partial, epileptic seizures (partial seizures with or without secondary generalization);
- treatment and prevention of bipolar affective disorders. In children, as monotherapy or in combination with other antiepileptic drugs:
- treatment of generalized epileptic seizures (clonic, tonic, tonic-clonic, absences, myoclonic, atonic); Lennox-Gastaut syndrome;
- treatment of partial epileptic seizures (partial seizures with or without secondary generalization).

Hypersensitivity to valproic acid or to other components of the drug; acute hepatitis; chronic hepatitis; history of liver disease, porphyria; combination with mefloquine; combination with St. John's wort; children's age up to 3 years; not recommended for use in combination with lamotrigine. With caution - Inhibition of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia), organic brain diseases, liver and pancreas diseases in history; hypoproteinemia, mental retardation in children, congenital fermentopathy, renal failure.

Animal studies have shown teratogenic effects.
According to available data, in humans, valproic acid mainly causes a violation of the development of the neural tube: myelomeningocele, spina bifida (1-2%). Cases of facial dysmorphia and malformations of the limbs (especially shortening of the limbs), as well as malformations have been described. of cardio-vascular system.
The risk of malformations is higher with combined antiepileptic therapies than with valproic acid monotherapy.
Given the above, during pregnancy, the use of the drug is possible only if the intended benefit to the mother outweighs the potential risk to the fetus.
During pregnancy, antiepileptic treatment with valproate should not be interrupted. acid if it is effective. In such cases monotherapy is recommended; The minimum effective daily dose should be divided into two doses.
Drugs may be added in addition to antiepileptic therapy folic acid(at a dose of 5 mg / day), because. they minimize the risk of neural tube defects.
Valproic acid can cause hemorrhagic syndrome in newborns, which, apparently, is associated with hypofibrinogenemia. There have been cases of afibrinogenemia with a fatal outcome.
Valproic acid is excreted in breast milk in concentrations ranging from 1% to 10%. It is recommended to stop difficult feeding at the time of taking the drug.

Symptoms: coma with muscular hypotension, hyporeflexia, miosis, respiratory depression, metabolic acidosis; cases are described intracranial hypertension associated with cerebral edema.
Treatment: in the hospital - gastric lavage, if no more than 10-12 hours have passed after taking the drug; monitoring the state of the cardiovascular and respiratory systems and maintaining effective diuresis. In very severe cases, dialysis is performed. As a rule, the prognosis is favorable, but a few cases of death have been described.

Before starting treatment and during the first 6 months of therapy, periodic monitoring of liver function is necessary, especially in patients at risk.
Among the classical tests, the most important are tests that reflect protein synthesis in the liver, and especially the prothrombin index. With a significant decrease in the concentration of prothrombin, a pronounced decrease in the content of fibrinogen, blood clotting factors, an increase in the concentration of bilirubin and transaminase activity, treatment with Valparin ® XP should be suspended. If the patient receives salicylates at the same time, then they should also be immediately discontinued, since salicylates and valproic acid have common metabolic pathways.
The risk of developing side effects from the liver is increased during combined anticonvulsant therapy, as well as in children.
Early diagnosis is based primarily on clinical examination. In particular, two factors that may precede jaundice should be taken into account, especially in patients at risk:
- non-specific general symptoms, usually appearing suddenly, such as asthenia, anorexia, extreme fatigue, drowsiness, sometimes accompanied by recurrent vomiting and abdominal pain;
- relapse of epileptic seizures against the background of antiepileptic therapy.
It should: warn the patient, and if this is a child, then his family, about the need to immediately notify the doctor about the occurrence of these symptoms.
In addition to clinical examination in such cases, an immediate liver function test should be performed.
In rare cases, severe forms of pancreatitis, sometimes with a fatal outcome, have been noted.
These cases were observed regardless of the patient's age and duration of treatment, although the risk of developing pancreatitis decreased with increasing age of patients. Liver failure in pancreatitis increases the risk of death.
It should be emphasized that in the treatment of both Valparin ® XP and other antiepileptic drugs, there may be a slight isolated and temporary increase in transaminase activity, especially at the beginning of treatment, in the absence of any clinical symptoms. In this case, it is recommended to conduct a more complete examination (including, in particular, the determination of the prothrombin index) in order to revise the dose if necessary and repeat the tests depending on the change in parameters.
Before starting therapy, before surgery, in the event of hematomas or spontaneous bleeding, a complete blood count (including determining the number of platelets, bleeding time and coagulation parameters) is necessary.
If symptoms of an "acute" abdomen and gastrointestinal symptoms such as nausea, vomiting and / or anorexia occur during treatment, it is necessary to determine the activity of amylase in the blood to exclude acute pancreatitis. With increased activity of pancreatic enzymes, the drug should be discontinued, taking alternative therapeutic measures.
When using Valparin ® XP in patients with renal insufficiency, it is recommended to take into account the increased concentration of the free form of valproic acid in the blood plasma and reduce the dose.
If it is necessary to prescribe the drug to patients with systemic lupus erythematosus and other diseases immune system expected healing effect And, possible risk therapy, since the use of Valparin ® XP in extremely rare cases, there were violations of the immune system.
It is not recommended to prescribe the drug to patients with a deficiency of urea cycle enzymes. In such patients, several cases of hyperammonemia accompanied by stupor and/or coma have been described.
During treatment, drinks containing ethanol are not allowed.
Patients should be warned of the risk of weight gain at the start of treatment and advised to follow a diet to minimize such exposure.

Long-acting film-coated tablets, 300 mg, 500 mg. 10 tablets in an aluminum foil strip. 3, 5 or 10 strips together with instructions for use in a cardboard box.

Torrent Pharmaceuticals Ltd.
Torrent House, Off Ashram Road, Ahmedabad 380 009, India

Production site address:
Torrent Pharmaceuticals Ltd.
Indrad-3 82721, Diet. Mehsana, India
or
Torrent Pharmaceuticals Ltd.
Village: Bhud and Makhnu Majra, Tehsil: Buddi-173205, Diet.: Solan. (H.P.), India

For more information please contact:
Representative office of Torrent Pharmaceuticals Ltd.:
Moscow, 117418 st. Novocheremushkinskaya, 61

For one film-coated tablet:

Dosage:

film sheath:

* which corresponds to 300 mg of sodium valproate per 1 tablet.

** which corresponds to 500 mg of sodium valproate per 1 tablet.

White or almost white, oval biconvex film-coated tablets, white or almost white in cross section.

An antiepileptic drug that has a central muscle relaxant and sedative effect.

Valproic acid and its salt, sodium valproate, are derivatives of a group of fatty acids. The most likely mechanism of action is an increase in the inhibitory effect of gamma-aminobutyric acid (GABA, GABA) due to the impact on its synthesis and subsequent metabolism.

Absorption

Bioavailability of sodium valproate and valproic acid in blood oral administration close to 100%.

When taking valproic acid at a dose of 1000 mg / day, the minimum plasma concentration(Cmin) is 44.7±9.8 µg/ml, and the maximum plasma concentration (C m ah ) - 81.6±15.8 µg/ml. Maximum plasma concentration (T s m ah ) is reached after about 6.58 ± 2.23 hours, and the equilibrium concentration - within 3-4 days of regular intake.

The therapeutic concentration range for valproic acid is 50 mg/L to 100 mg/L (equivalent to 278-694 µM/L). At concentrations above 100 mg/l, an increase in side effects is expected up to the development of intoxication. At plasma concentrations above 150 mg / l, a dose reduction is required.

Distribution

The volume of distribution depends on age (in the elderly - higher) and is usually 0.13-0.23 l / kg of body weight; in young people 0.13-0.19 l / kg of body weight. Communication with blood plasma proteins (mainly with albumin) is high (90-95%), dose-dependent and saturable. In elderly patients, patients with renal and hepatic insufficiency, the connection with blood plasma proteins decreases, and in severe renal insufficiency, the level of the free fraction of valproic acid may increase to 8.5-20%.

With hypoproteinemia, the total level of valproic acid (free + plasma protein-bound fraction) may remain unchanged, but may also decrease due to an increase in the metabolism of the free fraction of valproic acid.

The level of valproic acid in cerebrospinal fluid approximately corresponds to the level of the free fraction, which is about 10% of the total concentration. excreted in the breast milk of nursing mothers. The equilibrium concentration of valproic acid in breast milk is from 1% to 10% of its concentration in blood serum.

Metabolism

Metabolism of valproic acid is carried out in at least three ways: in the liver by glucuronidation (about 50% of the total content of the drug), beta-, omega-, and omega-1 oxidation (about 40%) and cytochrome P450-mediated oxidation (about 10 %). More than 20 metabolites have been identified, and the metabolites formed as a result of mitochondrial oxidation are hepatotoxic. , unlike most other antiepileptic drugs, does not induce microsomal liver enzymes, and therefore does not affect the degree of both its own metabolism and the degree of metabolism of other substances, such as estrogens, progestogens and indirect anticoagulants.

breeding

Valproic acid is predominantly excreted by the kidneys after conjugation with glucuronic acid and beta-oxidation. Less than 5% of valproic acid is excreted by the kidneys unchanged. The plasma clearance of valproic acid in patients with epilepsy is 12.7 ml/min.

The half-life of valproic acid is usually in the range of 8 to 20 hours, usually 15 to 17 hours. The value of the half-life in children over 2 months of age is close to those in adults.

In patients with renal insufficiency, dose adjustment may be required depending on the plasma concentration of the drug. The amount of free drug is usually 6-15% of general level valproic acid in plasma, while pharmacological effect the drug is not always in a clear relationship with the total level of valproic acid in plasma or the amount of free substance.

When combined with antiepileptic drugs that induce microsomal liver enzymes, the plasma clearance of valproic acid increases, and the half-life decreases, the degree of their change depends on the degree of induction of microsomal liver enzymes by other antiepileptic drugs.

In patients with liver disease, the half-life of valproic acid is increased. In case of overdose, an increase in the half-life up to 30 hours was observed. Only the free fraction of valproic acid in the blood (10%) is subjected to hemodialysis.

Features of pharmacokinetics during pregnancy

With an increase in the volume of distribution of valproic acid in the third trimester of pregnancy, its renal clearance increases. At the same time, despite taking the drug at a constant dose, a decrease in serum concentrations of valproic acid is possible. In addition, during pregnancy, the relationship of valproic acid with plasma proteins may change, which can lead to an increase in the content of the free (therapeutically active) fraction of valproic acid in the blood serum.

Compared to the enteric-coated form, the extended-release form at equivalent doses is characterized by the following: no absorption delay time after ingestion; prolonged absorption; identical bioavailability; lower maximum concentration, (decrease in maximum concentration by about 25%), but with a more stable plateau phase from 4 to 14 hours after ingestion; more linear correlation between dose and plasma drug concentration.

Pregnancy

Risk, associated with the development of epileptic seizures during pregnancy

During pregnancy, the development of generalized tonic-clonic epileptic seizures, status epilepticus with the development of hypoxia may pose a particular risk, both for the mother and the fetus, due to the possibility of death.

The risk associated with the use of the drug during pregnancy

Experimental reproductive toxicity studies in mice, rats, and rabbits have demonstrated that valproic acid is teratogenic.

Congenital malformations

The available clinical data have demonstrated a higher incidence of minor and severe malformations, in particular, congenital neural tube defects, craniofacial deformities, malformations of the limbs and the cardiovascular system, hypospadias, and multiple malformations affecting different organ systems in children born to mothers who took valproic acid during pregnancy, compared with their frequency when taken during pregnancy 7 of a number of other antiepileptic drugs. Thus, the risk of congenital malformations in children born to mothers with epilepsy who received valproic acid monotherapy during pregnancy was approximately 1.5, 2.3, 2.3 and 3.7 times higher compared with phenytoin monotherapy, carbamazepine, phenobarbital and lamotrigine, respectively.

Data from a meta-analysis that included registry and cohort studies showed that the incidence of congenital malformations in children born to mothers with epilepsy who received valproic acid monotherapy during pregnancy was 10.73% (95% confidence interval 8.16 - 13, 29). This risk is greater than the risk of severe congenital malformations in the general population, which was 2-3%. This risk is dose-dependent, but it is not possible to establish a threshold dose below which there is no such risk.

Disorders of mental and physical development

It has been shown that intrauterine exposure to valproic acid may have undesirable effects on the mental and physical development of children exposed to such exposure. Apparently, this risk is dose-dependent, but it is not possible to establish a threshold dose below which there is no such risk. The exact gestational period for the risk of developing these effects has not been established, and the risk cannot be ruled out throughout pregnancy. Children's research preschool age exposed to valproic acid in utero showed that up to 30-40% of these children had early developmental delays (such as delayed learning to walk and delayed speech development), as well as lower intellectual abilities, poor speech skills (own speech and speech understanding ) and memory problems. IQ (index I.Q.), determined in children aged 6 years with a history of intrauterine exposure to valproate was on average 7-10 points lower than in children exposed to intrauterine exposure to other antiepileptic drugs. Although the role of other factors that can undesirably affect the intellectual development of children exposed to valproic acid in utero cannot be ruled out, it is clear that in such children the risk of intellectual impairment may be independent of the index mother's IQ.

Data on long-term outcomes are limited.

There is evidence that children exposed to valproic acid in utero have an increased risk of developing spectrum 8 autism spectrum disorders (approximately a three to fivefold increase in risk), including childhood autism. Limited evidence suggests that children exposed to valproic acid in utero are more likely to develop attention deficit/hyperactivity disorder (ADHD).

Valproic acid monotherapy and valproic acid combination therapy are associated with poor pregnancy outcomes, but combination antiepileptic therapy with valproic acid has been reported to be associated with a higher risk of adverse pregnancy outcome compared to valproic acid monotherapy (i.e., risk of the development of disorders in the fetus is less with the use of valproic acid in monotherapy).

Risk factors for fetal malformations are: a dose of more than 1000 mg / day (however, a lower dose does not eliminate this risk) and the combination of valproic acid with other anticonvulsants. In connection with the foregoing, the drug should not be used during pregnancy and in women of childbearing potential unless absolutely necessary, that is, its use is possible in situations where other antiepileptic drugs are ineffective or the patient does not tolerate them.

The question of the need to use the drug or the possibility of refusing to use it should be decided before starting the use of the drug or reconsidered if the woman taking the drug is planning a pregnancy. Women of childbearing potential should use effective methods contraception during treatment with valproic acid.

Women of childbearing potential should be informed about the risks and benefits of using valproic acid during pregnancy.

If a woman is planning a pregnancy, or she is diagnosed with pregnancy, then the need for treatment with valproic acid should be reassessed depending on the indication (see below).

- When bipolar disorder is indicated, consideration should be given to discontinuing treatment with valproic acid.

- When epilepsy is indicated, the question of continuing treatment with valproic acid or its withdrawal is decided after a reassessment of the benefit-risk ratio. If, after a reassessment of the benefit-risk ratio, treatment with the drug should still be continued during pregnancy, then it is recommended to use it in the minimum effective daily dose, divided into several doses. It should be noted that during pregnancy, the use of sustained release dosage forms is more preferable than other dosage forms.

If possible, supplementation with folic acid (5 mg per day) should be started even before pregnancy, as it may reduce the risk of neural tube defects. However, currently available data do not support its preventive effect on congenital malformations that occur under the influence of valproic acid.

A continuous (including in the third trimester of pregnancy) special prenatal diagnostics should be carried out to identify possible malformations of the neural tube or other fetal malformations, including a detailed ultrasound examination.

Risk for newborns

It was reported about the development of isolated cases of hemorrhagic syndrome in newborns whose mothers took valproic acid during pregnancy. This hemorrhagic syndrome is associated with thrombocytopenia, hypofibrinogenemia, and/or a decrease in other blood clotting factors. Afibrinogenemia has also been reported, which could be fatal. This hemorrhagic syndrome should be distinguished from vitamin K deficiency caused by phenobarbital and other inducers of microsomal liver enzymes.

Therefore, in newborns whose mothers received treatment with valproic acid during pregnancy, coagulation tests should be performed (determine the number of platelets in peripheral blood, plasma fibrinogen concentration, blood clotting factors and a coagulogram).

Cases of hypoglycemia have been reported in newborns whose mothers took valproic acid during the third trimester of pregnancy.

Cases of hypothyroidism have been reported in newborns whose mothers took valproic acid during pregnancy.

Neonates whose mothers took valproic acid in the last trimester of pregnancy may experience withdrawal syndrome (in particular, the appearance of agitation, irritability, hyperreflexia, trembling, hyperkinesia, muscle tone disorders, tremors, convulsions and difficulty feeding).

Fertility

In connection with the possibility of developing dysmenorrhea, amenorrhea, polycystic ovaries, an increase in the concentration of testosterone in the blood, a decrease in fertility in women is possible (see section "Side Effects"). In men, it can reduce sperm motility and impair fertility (see section "Side Effects"). These fertility disorders have been found to be reversible after discontinuation of treatment.

Period breastfeeding

Excretion of valproic acid into breast milk is low, its concentration in milk is 1-10% of its concentration in blood serum.

There are limited clinical data on the use of valproic acid during breastfeeding, and therefore, the use of the drug during this period is not recommended.

Based on literature data and little clinical experience, breastfeeding with valproic acid monotherapy may be considered, but the side effect profile of the drug, especially the haematological disorders it causes, should be taken into account.

This drug intended only for adults and children over 6 years of age weighing more than 17 kg!

The drug is a dosage form of prolonged release active substance. Prolonged release avoids sharp rises in the concentration of valproic acid in the blood after taking the drug and maintains a constant concentration of valproic acid in the blood for a longer period of time.

Valproic Acid 300mg/500mg Extended Release Tablets may be divided to facilitate individual dose adjustment.

Tablets are taken without crushing or chewing them.

Dosing regimen for epilepsy

The minimum effective dose to prevent the development of epileptic seizures should be selected (especially during pregnancy). The daily dose should be adjusted according to age and body weight. A stepwise (gradual) dose increase is recommended until the minimum effective dose is reached.

A clear relationship between daily dose, plasma concentration and therapeutic effect has not been established. Therefore, the optimal dose should be determined primarily by clinical response. Determination of the concentration of valproic acid in plasma can serve as an addition to clinical observation if epilepsy is not controlled or there is a suspicion of the development of side effects. The range of therapeutic concentration in the blood is usually 40 - 100 mg/l (300 - 700 µmol/l).

With monotherapy, the initial daily dose is usually 5-10 mg of valproic acid per kg of body weight, which is then gradually increased every 4-7 days at the rate of 5 mg of valproic acid per kg of body weight to the dose necessary to achieve control of epileptic seizures.

Average daily doses (with long-term use):

- for children 6-14 years old (body weight 20-30 kg) - 30 mg valproic acid / kg body weight (600-1200 mg);

- for adolescents (body weight 40-60 kg) - 25 mg valproic acid / kg body weight (1000-1500 mg);

- for adults and elderly patients (body weight from 60 kg and above) - an average of 20 mg of valproic acid / kg of body weight (1200-2100 mg).

Although the daily dose is determined depending on the age and body weight of the patient; should be taken into account wide range individual sensitivity to valproate.

If epilepsy is not controlled at such doses, they can be increased under the control of the patient's condition and the concentration of valproic acid in the blood. In some cases, complete therapeutic effect valproic acid does not appear immediately, but develops within 4-6 weeks. Therefore, do not increase the daily dose above the recommended average daily dose before this time.

The daily dose may be divided into 1-2 doses, preferably with meals. One-shot use is possible with well-controlled epilepsy.

When switching from valproate immediate-release tablets the daily dose, which provided the necessary control over the disease, should be maintained when switching to taking extended-release tablets.

For patients who have previously taken antiepileptic drugs, the transition to taking the drug Valproic acid should be carried out gradually, reaching the optimal dose of the drug within about 2 weeks. At the same time, the dose of the previously taken antiepileptic drug is immediately reduced, especiallyphenobarbital. If a previously taken antiepileptic drug is canceled, then its cancellation should be carried out gradually.

Since other antiepileptic drugs can reversibly induce microsomal liver enzymes, blood levels of valproic acid should be monitored within 4-6 weeks after taking the last dose of these antiepileptic drugs and, if necessary (as the metabolism-inducing effect of these drugs decreases), reduce the daily dose. valproic acid.

If necessary, the combination of valproic acid with other antiepileptic drugs should be added to the treatment gradually.

To indicate the frequency of development of adverse reactions(HP) World Health Organization classification used: very common ≥ 10%; often ≥ 1% and< 10 %; нечасто ≥ 0,1 % и < 1 %; редко ≥ 0,01 % и < 0,1 %; очень редко < 0,01 %; частота неизвестна (когда по имеющимся данным оценить частоту развития HP does not seem possible).

Congenital, hereditary and genetic disorders

Teratogenic risk (see section "Use during pregnancy and lactation").

Blood and lymphatic system disorders

Often:anemia, thrombocytopenia (see section "Special Instructions").

Infrequently:pancytopenia, leukopenia, neutropenia.

Leukopenia and pancytopenia may be similar to depression bone marrow, and without it. After discontinuation of the drug, the blood picture returns to normal.

Seldom: disorders of bone marrow hematopoiesis, including isolatederythrocyte plasia / hypoplasia, agranulocytosis, macrocytic anemia, macrocytosis; a decrease in the content of blood coagulation factors (at least one), a deviation from the norm of indicators of blood coagulation (such as an increase in prothrombin time, an increase in activated partial thromboplastin time, an increase in thrombin time, an increase in INR [international normalized ratio]) (see sections "Use for pregnancy and during breastfeeding" and "Special Instructions"). The appearance of spontaneous ecchymosis and bleeding indicates the need to discontinue the drug and conduct an examination.

Laboratory and instrumental data

Seldom:biotin deficiency/deficiency of biotinidase.

Nervous System Disorders

Often: tremor.

Often:extraniramidal disorders, stupor*, drowsiness, convulsions*, memory impairment, headache, nystagmus; dizziness (with intravenous administration dizziness may occur within a few minutes and resolve spontaneously within a few minutes).

Infrequently:coma*, encephalopathy*, lethargy*, reversible parkinsonism, ataxia, paresthesia.

Seldom:reversible dementia, combined with reversible brain atrophy, cognitive disorders.

Frequency unknown: sedation.

*Stupor and lethargy sometimes led to transient coma/encephalopathy and were either isolated or associated with an increase in seizures during treatment, and also improved when the drug was discontinued or when the dose was reduced. Most of these cases have been described against the background of combination therapy, especially with the simultaneous use of phenobarbital or topiramate, or after a sharp increase in the dose of valproic acid.

Hearing and labyrinth disorders

Often:reversible and irreversible deafness.

Violations of the organ of vision

Frequency unknown: diplopia.

Respiratory disorders , chest and mediastinum

Infrequently:pleural effusion.

Digestive system disorders

Often: nausea.

Often:vomiting, gingival changes (mainly gingival hyperplasia), stomatitis, epigastric pain, diarrhea, which often occur in some patients at the beginning of treatment, but usually disappear after a few days and do not require discontinuation of therapy. Frequent reactions from the digestive system can be reduced by taking the drug during or after a meal.

Infrequently:pancreatitis, sometimes fatal (the development of pancreatitis is possible during the first 6 months of treatment; in case of acute abdominal pain, it is necessary to control the activity of serum amylase, see the section "Special Instructions".

Frequency unknown: abdominal cramps, anorexia, increased appetite.

Nocturnal disorders and urinary tract

Infrequently:kidney failure.

Seldom:enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (a complex of biochemical and clinical manifestations of damage to the proximal renal tubules with impaired tubular reabsorption of phosphate, glucose, amino acids and bicarbonate), the development mechanism of which is still unclear.

Skin and subcutaneous tissue disorders

Often:hypersensitivity reactions, for example, urticaria, itching; transient(reversible) and / or dose-dependent pathological hair loss (alopecia), including androgenetic alopecia against the background of developed hyperandrogenism, polycystic ovaries (see subsections "Genital and breast disorders" and "Endocrine disorders" below), and also alopecia on the background of developed hypothyroidism (see subsection "Disorders of the endocrine system" below), disorders of the nails and the nail bed.

Infrequently:angioedema, rash, hair disorders (such as a violation of the normal structure of the hair, a change in hair color, abnormal hair growth [the disappearance of waviness and curly hair, or, conversely, the appearance of curly hair in individuals with initially straight hair]), hirsutism, acne.

Seldom: toxic epidermal necrolysis, Stevens-Johnson syndrome,erythema multiforme, drug rash syndrome with eosinophilia and systemic symptoms(DRESS syndrome).

Disorders of the musculoskeletal and connective tissue

Infrequently:decrease in bone mineral density, osteopenia, osteoporosis and fractures in patients taking valproic acid preparations for a long time. The mechanism of the effect of the drug on bone metabolism has not been established.

Seldom:systemic lupus erythematosus (see section "Special instructions"), rhabdomyolysis (see section "With caution", "Special instructions").

Endocrine Disorders

Infrequently:syndrome of inappropriate secretion of antidiuretic hormone (SIADH), hyperandrogenism (hirsutism, virilization, acne, male pattern alopecia and / or increased concentrations of androgens in the blood).

Seldom:hypothyroidism (see section "Use during pregnancy and breastfeeding").

Metabolic and litanium disorders

Often:hyponatremia, weight gain (weight gain should be carefully monitored, as weight gain is a factor contributing to the development of polycystic ovary syndrome).

Seldom:hyperammonemia * (see section "Special Instructions"), obesity.

*There may be cases of isolated and moderate hyperammonemia without changes in liver function tests that do not require discontinuation of treatment. It was also reported about the occurrence of hyperammonemia, accompanied by the appearance of neurological symptoms (for example, the development of encephalopathy, vomiting, ataxia, and other neurological symptoms), which required discontinuation of valproic acid and an additional examination (see section "Special Instructions").

Clinical manifestations of acute massive overdose usually occur in the form of a coma with muscle hypotension, hyporeflexia, miosis, respiratory depression, metabolic acidosis, excessive decrease in blood pressure and vascular collapse/shock.

Cases of intracranial hypertension associated with cerebral edema have been described.

The presence of sodium in the composition of valproic acid preparations in case of their overdose can lead to the development of hypernatremia.

With a massive overdose, a fatal outcome is possible, but the prognosis for an overdose is usually favorable.

Symptoms of overdose may vary; seizures have been reported at very high plasma concentrations of valproic acid.

Overdose treatment

Urgent care in case of overdose in the hospital should be as follows: gastric lavage, which is effective for 10-12 hours after taking the drug. To reduce the absorption of valproic acid, it may be effective to take activated charcoal, including its administration through a nasogastric tube. It requires monitoring the state of the cardiovascular and respiratory systems and maintaining effective diuresis. It is necessary to control the functions of the liver and pancreas. Respiratory depression may require artificial ventilation lungs. In some cases, it has been successfully used. In very severe cases of massive overdose, hemodialysis and hemoperfusion have been effective.

The effect of valproic acid on other drugs

Antipsychotics, monoamine oxidase (MAO) inhibitors, antidepressants, benzodiazepines

Valproic acid may potentiate the action of other psychotropic drugs such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; therefore, when they are used simultaneously with valproic acid, careful medical supervision and, if necessary, dose adjustment is recommended.

Lithium preparations

Valproic acid does not affect serum lithium concentrations.

Phenobarbital

Valproic acid increases plasma concentrations of phenobarbital (by reducing its hepatic metabolism), and therefore the development of a sedative effect of the latter is possible, especially in children. Therefore, careful medical monitoring of the patient during the first 15 days of combination therapy is recommended, with an immediate reduction in the dose of phenobarbital in the event of a sedative effect and, if necessary, the determination of plasma concentrations of phenobarbital.

primidon

Valproic acid increases plasma concentrations of primidone with an increase in its side effects (such as sedation); with prolonged treatment, these symptoms disappear. Careful clinical monitoring of the patient is recommended, especially at the beginning of combination therapy, with dose adjustment of primidone if necessary.

Phenytoin

Valproic acid reduces total plasma concentrations of phenytoin. In addition, it increases the concentration of the free fraction of phenytoin with the possibility of developing overdose symptoms (displaces it from the connection with plasma proteins and slows down its hepatic catabolism). Therefore, careful clinical monitoring of the patient and determination of the concentrations of phenytoin and its free fraction in the blood is recommended.

Carbamazepine

With the simultaneous use of valproic acid and carbamazepine, clinical manifestations of carbamazepine toxicity have been reported, since it can potentiate the toxic effects of carbamazepine. Careful clinical monitoring of such patients is recommended, especially at the beginning of combination therapy with correction, if necessary, of the dose of carbamazepine. Lamotrigine

Valproic acid slows down the metabolism of lamotrigine in the liver and increases the half-life of lamotrigine by almost 2 times. This interaction can lead to increased toxicity of lamotrigine, in particular, to the development of severe skin reactions, including toxic epidermal necrolysis. Therefore, careful clinical observation and, if necessary, dose adjustment (reduction) of lamotrigine is recommended.

Zidovudine

Valproic acid may increase plasma concentrations of zidovudine, resulting in increased zidovudine toxicity.

Felbamate

Valproic acid can reduce the mean clearance of felbamate by 16%. Olanzapine

Valproic acid may decrease plasma concentrations of olanzapine.

Rufinamide

Valproic acid can lead to an increase in the plasma concentration of rufinamide. This increase depends on the concentration of valproic acid in the blood. Caution should be exercised, especially in children, as this effect is more pronounced in this population.

Nimodipine (oral and, by extrapolation, parenteral solution)

Strengthening the hypotensive effect of nimodipine due to an increase in its plasma concentration (inhibition of the metabolism of nimodipine by valproic acid).

Temozolomide

Co-administration of temozolomide with valproic acid results in a mild but statistically significant decrease in the clearance of temozolomide.

The effect of other drugs on valproic acid

Antiepileptic drugs that can induce microsomal liver enzymes (including,) reduce plasma concentrations of valproic acid. In the case of combination therapy, the doses of valproic acid should be adjusted depending on the clinical response and the concentration of valproic acid in the blood.

The concentration of metabolites of valproic acid in the blood serum may be increased if it is used simultaneously with phenytoin or phenobarbital. Therefore, patients treated with these two drugs should be closely monitored for signs and symptoms of hyperammonemia, as some metabolites of valproic acid may inhibit urea cycle enzymes.

Felbamate

With the combination of felbamate and valproic acid, the clearance of valproic acid is reduced by 22-50% and, accordingly, plasma concentrations of valproic acid increase. Plasma concentrations of valproic acid should be monitored.

Mefloquine

Mefloquine accelerates the metabolism of valproic acid and is itself capable of causing convulsions, therefore, with their simultaneous use, the development of an epileptic seizure is possible.

Hypericum perforatum preparations

With the simultaneous use of valproic acid and preparations of St. John's wort, a decrease in the anticonvulsant effectiveness of valproic acid is possible.

Preparations, having a high and strong connection with plasma proteins ()

In the case of simultaneous use of valproic acid and drugs that have a high and strong relationship with plasma proteins (), it is possible to increase the concentration of the free fraction of valproic acid.

Indirect anticoagulants, including other coumarin derivatives

With the simultaneous use of valproic acid and indirect anticoagulants, careful monitoring of the prothrombin index is required.

Cimetidine, erythromycin

Serum concentrations of valproic acid may increase in the case of simultaneous use of cimetidine or erythromycin (as a result of slowing down its hepatic metabolism).

Carbapenems (panipenem, imipenem)

Decrease in the concentration of valproic acid in the blood during its simultaneous use with carbapenems: in two days of joint therapy, a 60-100% decrease in the concentration of valproic acid in the blood was observed, which was sometimes combined with the occurrence of seizures. The simultaneous use of carbapenems in patients with a selected dose of valproic acid should be avoided due to their ability to quickly and intensively reduce the concentration of valproic acid in the blood. If treatment with carbapenems cannot be avoided, blood levels of valproic acid should be carefully monitored.

Rifampicin

Rifampicin can reduce the concentration of valproic acid in the blood, which leads to the loss of the therapeutic effect of valproic acid. Therefore, it may be necessary to increase the dose of valproic acid while using rifampicin.

Protease inhibitors

Protease inhibitors, such as lopinavir, reduce the plasma concentration of valproic acid when used concomitantly.

Colestyramine

Colestyramine can lead to a decrease in plasma concentrations of valproic acid when used simultaneously with it.

Other interactions

With topiramate or acetazolamide

The concomitant use of valproic acid and topiramate or acetazolamide has been associated with encephalopathy and/or hyperammonemia. Patients taking these drugs concomitantly with valproic acid should be under close medical supervision for the development of symptoms of hyperammoniemic encephalopathy.

With quetiapine

The simultaneous use of valproic acid and quetiapine may increase the risk of developing neutropenia / leukopenia.

With estrogen-progestogen drugs

Valproic acid does not have the ability to induce liver enzymes and, as a result, does not reduce the effectiveness of estrogen-progestogenic drugs in women using hormonal methods of contraception.

With ethanol and other potentially hepatotoxic drugs

When they are used simultaneously with valproic acid, it is possible to increase the hepatotoxic effect of valproic acid.

With clonazepam

The simultaneous use of clonazepam with valproic acid can lead in isolated cases to an increase in the severity of the absence status.

With myelotoxic drugs

With their simultaneous use with valproic acid, the risk of inhibition of bone marrow hematopoiesis increases.

Before starting the use of the drug and periodically during the first 6 months of treatment, especially in patients at risk of developing liver damage, a study of liver function should be performed.

As with the use of most antiepileptic drugs, with the use of valproic acid, a slight increase in the activity of "liver" enzymes is possible, especially at the beginning of treatment, which proceeds without clinical manifestations and is transient. In these patients, a more detailed study of biological parameters, including the prothrombin index, is necessary, and dose adjustment of the drug may be required, and, if necessary, repeated clinical and laboratory examinations.

Before starting therapy or before surgery, as well as in case of spontaneous occurrence of subcutaneous hematomas or bleeding, it is recommended to determine the bleeding time, the number of formed elements in the peripheral blood, including platelets.

Severe liver damage

Predisposing factors

Clinical experience shows that patients at risk are patients taking several antiepileptic drugs at the same time; children under three years of age with severe seizures, especially against the background of brain damage, mental retardation and / or congenital metabolic or degenerative diseases; patients simultaneously taking salicylates (since salicylates are metabolized along the same metabolic pathway as).

After three years of age, the risk of liver damage is significantly reduced and progressively decreases as the age of the patient increases. In most cases, such liver damage occurred within the first 6 months of treatment, most often between 2 and 12 weeks of treatment, and usually with the use of valproic acid as part of a combination antiepileptic therapy.

Symptoms suggestive of liver damage

For early diagnosis Liver damage requires clinical monitoring of patients. In particular, attention should be paid to the appearance the following symptoms, which may precede the onset of jaundice, especially in patients at risk (see above):

- non-specific symptoms, especially sudden onset, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes accompanied by repeated vomiting and abdominal pain;

- recurrence of seizures in patients with epilepsy.

Patients or their family members (when using the drug in children) should be warned that they should immediately report the occurrence of any of these symptoms to the attending physician. Patients should immediately undergo a clinical examination and laboratory testing of liver function tests.

Revealing

Determination of liver function tests should be carried out before starting treatment and then periodically during the first 6 months of treatment. Among conventional studies, the most informative studies reflect the state of the protein-synthetic function of the liver, especially the determination of the prothrombin index. Confirmation of an abnormal prothrombin index, especially in combination with abnormalities of other laboratory parameters (a significant decrease in the content of fibrinogen and blood coagulation factors, an increase in the concentration of bilirubin and an increase in the activity of "liver" transaminases), as well as the appearance of other symptoms indicating liver damage ( see above), requires discontinuation of the drug. As a precaution, if patients were taking salicylates at the same time, their intake should also be discontinued.

The use of valproic acid may provide the level of seizure control necessary for driving a motor vehicle.

However, the drug also causes drowsiness, especially when combined therapy or when joint application with benzodiazepines (see section " Interaction with other drugs"), Therefore, patients during treatment should be careful when driving vehicles and engaging in other activities that require increased concentration of attention and speed of psychomotor reactions.

Prolonged release tablets, coated, 300 mg, 500 mg.

30 or 100 tablets in desiccant bottles with plastic caps.

Each bottle, together with instructions for use, is placed in a box of cardboard boxes.

In a place protected from light at a temperature not exceeding 25 ° C.

Keep out of the reach of children.